ABSTRACT Only three medications are FDA-approved to treat Alcohol Use Disorder (AUD), and replicable patient-level predictors of medication response remain elusive. Thus, evaluation of novel medications in a precision medicine framework is needed to advance AUD treatment. At its most severe stage, AUD is characterized by dysregulated cortical inhibition of striatal reward signaling, leading to preoccupation with alcohol and loss of control over drinking. This phenomenon is accompanied by changes in multiple neurotransmitter systems, including dopamine (DA) and serotonin (5-HT). Several serotonin/dopamine activity modulators (SDAMs), which act at D2, D3, 5-HT1A, and 5-HT2A receptors, have been explored as AUD treatments. Of these compounds, aripiprazole (APZ) has displayed the most promise, but variable efficacy and concerns about its tolerability have reduced enthusiasm for further study. In our preliminary data, we conducted a human lab study of APZ in which we demonstrated that variation at a variable number tandem repeat (VNTR) polymorphism in the gene encoding the DA transporter (DAT), DAT1/SLC6A3, moderated APZ effects on alcohol cue-elicited brain activation and drinking in a bar-lab paradigm. Specifically, APZ reduced these outcomes only among DAT1 9R carriers (i.e., those predisposed to higher basal DA tone). However, interpretation of findings was limited because participants were lower severity non-treatment-seekers, DAT1 genotype was not used for prospective randomization, and APZ effects on cortical processing were not tested. Further, APZ caused increased adverse effects despite the use of a lower dose than previously tested. This project aims to build upon our preliminary data by testing the effects of a novel SDAM, brexpiprazole (BREX), in a pharmacogenetic human laboratory paradigm. BREX is an FDA-approved SDAM with similar molecular targets as APZ (D2, D3, and 5-HT1A agonism and 5-HT2A antagonism) but enhanced serotonergic and noradrenergic effects and an improved adverse effect profile. A group of non-treatment-seeking individuals with higher severity AUD will be recruited and prospectively randomized, on the basis of their DAT1 VNTR genotype, to one of two doses of BREX, or matched placebo, for fourteen days. Our primary aims are to evaluate the effect of BREX on 1) brain activation associated with response inhibition and alcohol cue reactivity and 2) drinking in the natural environment and in a bar-lab paradigm, and to determine whether DAT1 genotype predicts these effects. Secondarily, we will explore whether BREX effects on inhibition-related cortical activation or cue-elicited VS activation mediate its effects on drinking. Achievement of these aims will potentially advance BREX as a new treatment option for AUD, indicate a subgroup for whom it may be most effective, and/or offer information about BREX?s potential mechanism of action in reducing drinking.